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Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

ABSTRACT: Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

PROVIDER: PRJNA521251 | ENA |

REPOSITORIES: ENA

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Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice

2019-04-02 | GSE126184 | GEO

Adaptive plasticity of IL10 + and IL35 + regulatory T cells

Project description:Regulatory T cells (T regs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. T regs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; Ebi3/IL12α heterodimer) are divergently expressed by T reg subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. T reg -restricted deletion of Il10 and/or Ebi3 resulted in delayed tumor growth, loss of multi-IR expression, and reduced intratumoral CD8 + T cell exhaustion signature. While Il10 or Ebi3 loss was associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1), IL10 and IL35 differentially impacted effector versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for IL10 and IL35, produced by limits effective anti-tumor immunity

2019-04-02 | GSE127735 | GEO

NLRP3 deficiency reverts intratumoral T cell exhaustion

Project description:NLRP3 deficiency reverts intratumoral T cell exhaustion

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NLRP3 deficiency reverts intratumoral T cell exhaustion

Project description:CD8+ T cells derived from mice with intact NLRP3 signaling in the tumor microenvironment showed an increased expression of coinhibitory receptors PD-1, TIM-3, 2B4 and LAG-3 compared to CD8+ T cells from PancOVA-bearing Nlrp3-/- mice, indicating that NLRP3 inflammasome activation in the tumor microenvironment mediates IL-18 receptor signaling-induced T cell exhaustion. RNAseq was used to characterised molecular pathways involved in T cell plasticity in the presence and absence of intratumoral NLRP3.

2022-04-14 | GSE200570 | GEO

nCounter mouse immune exhaustion panel in 4t1 breast cancer treated with repeat intratumoral influenza vaccine

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Adaptive plasticity of IL10 + and IL35 + regulatory T cells

Project description:Adaptive plasticity of IL10 + and IL35 + regulatory T cells

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Intratumoral antigen-signalling traps CD8+ T cells to confine exhaustion to the tumour site (scRNA-Seq)

Project description:Immunotherapy advances have been hindered by difficulties tracking the behaviours of lymphocytes following antigen-signalling. Here we present the antigen-receptor signalling reporter (AgRSR) mouse to fate-map lymphocytes responding to antigen at specific times and locations, to determine the behaviour of T cells involved in the tumour immune response. Contrary to reports of ready egress of T cells out of the tumour, we find that intratumoral antigen-signalling traps CD8+ T cells in the tumour. These clonal populations expand and become increasingly exhausted over time. In contrast, antigen- signalled regulatory T cell (Treg) clonal populations readily recirculate out of the tumour. Consequently, intratumoral antigen-signalling acts as a gatekeeper to compartmentalize CD8+ T cell responses – even within the same clonotype, enabling immunity to confine exhaustion to a specific tissue site.

2024-05-25 | GSE266361 | GEO

IL-18R signaling affects transcriptional profile of intratumoral CTLs

Project description:We report that intratumoral IL-18R-deficient T cells show decreased T cell exhaustion in a murine pancreatic cancer model

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Intratumoral antigen-signalling traps CD8+ T cells to confine exhaustion to the tumour site (bulk TCR-Seq)

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IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets [IL10+ vs IL10-T helper cell RNA-seq]

Project description:IL-27 is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, Atf3) and 2 negative (Irf9, Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators Prdm1 and Maf that cooperatively drive the expression of signature genes induced by IL-27 in Type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3+regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying the ll10 deficient mice. Our work provides insights for IL-27 driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.

2020-12-21 | GSE158703 | GEO

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